Original Article
Comparison of frovatriptan plus dexketoprofen (25 mg or 37.5 mg) with frovatriptan alone in the treatment of migraine attacks with or without aura: A randomized study
Cephalalgia 2014, Vol. 34(6) 434–445 ! International Headache Society 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102413515342 cep.sagepub.com
Vincenzo Tullo1, Fabio Valguarnera2, Piero Barbanti3, Pietro Cortelli4, Giuliano Sette5, Gianni Allais6, Florindo d’Onofrio7, Marcella Curone1, Dario Zava8, Deborha Pezzola8, Chiara Benedetto6, Fabio Frediani9 and Gennaro Bussone1 Abstract Background: Drugs for migraine attacks include triptans and NSAIDs; their combination could provide greater symptom relief. Methods: A total of 314 subjects with history of migraine, with or without aura, were randomized to frovatriptan 2.5 mg alone (Frova), frovatriptan 2.5 mg þ dexketoprofen 25 mg (FroDex25) or frovatriptan 2.5 mg þ dexketoprofen 37.5 mg (FroDex37.5) and treated at least one migraine attack. This was a multicenter, randomized, double-blind, parallel-group study. The primary end point was the proportion of pain free (PF) at two hours. Secondary end points were PF at one and four hours, pain relief (PR) at one, two, four hours, sustained PF (SPF) at 24 and 48 hours, recurrence at 48 hours, resolution of nausea, photophobia and phonophobia at two and four hours, the use of rescue medication and the judgment of the treatment. Results: The results were assessed in the full analysis set (FAS) population, which included all subjects randomized and treated for whom at least one post-dose intensity of headache was recorded. The proportions of subjects PF at two hours (primary end point) were 29% (27/93) with Frova compared with 51% (48/95 FroDex25 and 46/91 FroDex37.5) with each combination therapies (p < 0.05). Proportions of SPF at 24 hours were 24% (22/93) for Frova, 43% (41/95) for FroDex25 (p < 0.001) and 42% (38/91) for FroDex37.5 (p < 0.05). SPF at 48 hours was 23% (21/93) with Frova, 36% (34/95) with FroDex25 and 33% (30/91) with FroDex37.5 (p ¼ NS). Recurrence was similar for Frova (22%, 6/27), FroDex25 (29%, 14/48) and FroDex37.5 (28%, 13/46) (p ¼ NS), meaning a lack of improvement with the combination therapy. Statistical adjustment for multiple comparisons was not performed. No statistically significant differences were reported in the occurrence of total and drug-related adverse events. FroDex25 and FroDex37.5 showed a similar efficacy both for primary and secondary end points. There did not seem to be a dose response curve for the addition of dexketoprofen. Conclusion: FroDex improved initial efficacy at two hours compared to Frova whilst maintaining efficacy at 48 hours in this study. Tolerability profiles were comparable. Intrinsic pharmacokinetic properties of the two single drugs contribute to this improved efficacy profile.
1
Department of Clinical Neuroscience, National Neurological Institute Carlo Besta, Italy 2 Sestri Ponente Hospital ‘‘Padre Antero Micone’’, Italy 3 Unit for treatment and research of headaches and pain, IRCCS San Raffaele Pisana, Italy 4 Neurological Clinic, Department of Neurological Science, University of Bologna, Italy 5 Sant’Andrea Hospital, Italy
6 Department of Gynecology and Obstetrics, Women’s Headache Center, University of Turin, Italy 7 San Giuseppe Moscati Hospital, Italy 8 Istituto Luso Farmaco d’Italia, Peschiera Borromeo, Italy 9 Ospedale S. Carlo Borromeo, Italy
Corresponding author: Vincenzo Tullo, Department of Clinical Neuroscience, National Neurological Institute Carlo Besta, Via Celoria 11, 20133 Milano, Italy. Email: [email protected]
435
Tullo et al. Keywords Frovatriptan, dexketoprofen, migraine attacks, triptans, NSAIDs Date received: 25 June 2013; revised: 6 August 2013; 13 September 2013; 7 October 2013; accepted: 11 October 2013
Introduction Migraine affects approximately 18% of women and 6% of men in Western countries (1). The prevalence peaks in subjects between 25 and 55 years old. The burden of migraine is enormous; in the United States (US) migraine sufferers spend a total of 112 million days bedridden and the annual cost of missed work or reduced productivity is $5.6 billion to $17.2 billion (1,2). The International Headache Society (IHS) criteria for diagnosing migraine (3) are the most widely used diagnostic criteria around the world. Drugs effective for treating migraine attacks include triptans, analgesics (such as nonsteroidal inflammatory drugs (NSAIDs)), ergot derivatives and antiemetics (4). Triptans, marketed in the early 1990s, were a major advance in the treatment of moderate-severe acute migraine attacks (4). They are selective 5-HT1B/D agonists. Seven triptans are available, being, theoretically, similar, but patients note differences in effectiveness and in tolerance (5). Frovatriptan is one of the newest triptans and its distinct pharmacokinetic and pharmacodynamics profile means that it has the clinical potential for a long duration of action and a low likelihood of side effects and drug interactions (6). The elimination half-life of frovatriptan is five times that of other triptans, while the time to maximum concentration (tmax) is similar to other triptans when given orally (5,7–10). NSAIDs and other simple analgesics are indicated for the treatment of mild or moderate migraine attacks (4). Dexketoprofen works by blocking the action of cyclooxygenase (COX), which is involved in the production of prostaglandins, and thereby reduces inflammation and pain (11,12). Dexketoprofen maximum plasma concentrations are observed around 30 minutes after an oral dose. Its elimination half-life, however, is quite short (13). Dexketoprofen proved to be effective and very fast in reducing pain intensity and accompanying symptoms in 42 women affected by migraine with or without aura (14). The complexity of the pathophysiology of migraine partially explains why none of the currently available monotherapies provides broad coverage of the multiple pathogenic processes in migraine (15–25).
A therapy that targets multiple mechanisms may confer advantages over monotherapy, and triptans and NSAIDs target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. This possibility is supported by the results of several clinical studies, including those on the concomitant use of sumatriptan succinate with naproxen sodium and rizatriptan with rofecoxib (26–30). The rationale for combining dexketoprofen with frovatriptan is linked to the intrinsic pharmacokinetic properties of the two drugs; dexketoprofen is absorbed rapidly and contributes to the early efficacy of the combination, whereas frovatriptan persists longer and so provides sustained efficacy with less recurrence. The aims of this study were to evaluate the efficacy and tolerability of the combination therapy frovatriptan plus dexketoprofen over frovatriptan alone in the acute treatment of migraine attacks.
Methods Study population The study recruited subjects of male or female gender, 18–65 years old, with a current history of migraine with or without aura, according to IHS 2004 criteria, and with at least one but no more than six migraine attacks per month for six months prior to entering the study. Figure 1 shows the study flowchart. Patients could not be enrolled in the study if they: (a) had coronary artery or cerebrovascular disease; (b) had uncontrolled hypertension; (c) had other types of headache in addition to migraine with or without aura; (d) were taking ergotamine (or its derivatives), St John’s Wort (Hypericum perforatum), monoamine oxidase (MAO)-inhibitors, NSAIDs (COX-2 inhibitors), oral corticosteroids, warfarin or other coumarins, selective serotonin reuptake inhibitors, or antiaggregant agents such as aspirin, heparin, lithium, methotrexate, hydantoins and sulphonamides; (e) had severe liver or renal impairment; (f) had a history of alcohol, analgesic or psychotropic drug abuse; (g) had known hypersensitivity to either of the study drugs or to any other NSAIDs; (h) had active peptic ulcer/bleeding or a history of gastrointestinal bleeding or perforation related to NSAID therapies; (i) had bronchial asthma; (j) were pregnant or breast feeding.
436
Cephalalgia 34(6)
PATIENTS SCREENED N = 321 - Violation of selection criteria (N = 2) - Other (N = 5) PATIENTS RANDOMIZED N = 314
PATIENTS ASSIGNED TO GROUP:
PATIENTS ASSIGNED TO GROUP:
PATIENTS ASSIGNED TO GROUP:
Frovatriptan
F + DXP 25 mg
F + DXP 37.5 mg
N = 106
N = 105
N = 103
COMPLETED
COMPLETED
COMPLETED
N = 106
N = 105
N = 103
Exclusion from FAS Population: - No attacks treated (N = 12) - Lack of efficacy data (N=1)
Exclusion from FAS Population: - No attacks treated (N = 10)
Exclusion from FAS Population: - No attacks treated (N = 11) - Lack of efficacy data (N=1)
FAS Population
FAS Population
FAS Population
N = 93
N = 95
N = 91
Exclusion from PP Population: - Prohibited treatments (N =4) - Inconsistency diaries (N=18) - Prohibited treatments+Diaries (N =1) - Lab test after V0+Diaries (N=1) - Prohibited treatments+wrong visit interval (N =2)
Exclusion from PP Population: - Prohibited treatments (N =2) - Inconsistency diaries (N=22) - Informed consent’s date not consistent (N=1) - Migraine attack after 30 days (=1) - Prohibited treatments+Migraine attack after 30 days (=1) - Prohibited treats+Diaries (N =3) - Wrong visit interval+Diaries (N=1)
Exclusion from PP Population: - Protocol criteria violation (N = 1) - Prohibited treatments (N =2) - Inconsistency diaries (N=13) - Informed consent’s date not consistent (N=1) - Prohibited treats+Diaries (N =2) - Wrong visit interval+Diaries (N=1)
PP Population
PP Population
PP Population
N = 67
N = 64
N = 71
Figure 1. Flow diagram of participants throughout the study. FAS: full analysis set; PP: per protocol; F: frovatriptan; DXP: dexketoprofen.
Written informed consent was obtained from all patients prior to their inclusion in the study. The study was approved by the independent institutional review boards of the centers in which the study
was carried out. The study was conducted according to the Declaration of Helsinki and Good Clinical Practice and was registered internationally (Eudract number 2009-011577-32).
437
Tullo et al.
Study design This was a multicenter, randomized, double-blind, active-controlled, three parallel-group, phase 3 study performed in 25 Italian centers from July 2009 to April 2010. Over-encapsulation was used to ensure blinding. This active treatment dose-comparison concurrent control study compared frovatriptan 2.5 mg þ dexketoprofen 25 mg (FroDex25) or frovatriptan 2.5 mg þ dexketoprofen 37.5 mg (FroDex37.5) to frovatriptan 2.5 mg þ placebo (Frova), in acute treatment of migraine with or without aura attacks in three parallel groups of 100 subjects each. The study protocol also foresaw a comparison between FroDex25 and FroDex37.5. After the screening visit, subjects were assigned by the investigators to one of the three treatment groups using randomization lists prepared by InnoPharma s.r.l. generated using three-subject blocks to balance the treatments. The lists were provided to all sites before the start of the study. Code-break envelopes were provided to the sites and could be opened in the case of an emergency. To keep the patients and study investigators blind to the treatment, the study drugs were over-encapsulated. Frovatriptan, dexketoprofen and placebo tablets were over-encapsulated in capsules suitable to keep the blinding. Two colors of capsules were used: white and red. The extemporary combination of frovatriptan 2.5 mg þ dexketoprofen 37.5 mg, frovatriptan 2.5 mg þ dexketoprofen 25 mg, frovatriptan 2.5 mg þ placebo was provided in indistinguishable carton boxes identified by the randomization numbers, each containing one treatment dose blister with two capsules: a red and a white one. All study end point parameters were recorded in a personal diary and, for the intensity of the headache attack, a four-point rating scale recommended by the IHS (0 ¼ no headache, 1 ¼ mild headache, 2 ¼ moderate headache, 3 ¼ severe headache) was used. Similar scales were used for assessment of the associated symptoms (nausea, photophobia and phonophobia). The active controlled design was chosen in accordance with guidelines on the choice of control groups in studies aimed at demonstrating superiority of a new treatment when an established treatment already exists (3,4). The two doses of 25 mg and 37.5 mg of dexketoprofen were chosen based on available literature data, and on the results from previous pre-clinical and clinical studies (12). The frovatriptan dose of 2.5 mg is the dose recommended in the SmPC (31). During the randomization visit, after signing written informed consent, subjects provided their clinical, medication and migraine history. Physical and neurological examinations and a pregnancy test (if appropriate) were performed. Blood pressure and heart rate
were measured for all subjects. The degree of migraine-associated disability was also determined, using the Migraine Disability Assessment (MIDAS) questionnaire. At the end of the visit a headache diary was dispensed with the study medication in order to document the characteristics of the headache pain and associated symptoms, and subjects were instructed to take the study medication and complete the diary for the first migraine attack that occurred during the study period (i.e. within one month from randomization). The study treatment was self-administered orally in single administration as early as possible after the onset of the migraine headache. During the study, three visits to the clinical center were scheduled: one at the screening, one at the randomization visit and a follow-up visit between 72 hours and 14 days (2) after the migraine attack.
Data analysis The primary efficacy variable to assess the possible superiority of frovatriptan plus dexketoprofen (high and low doses) over frovatriptan alone was the percentage of subjects pain free at two hours before any rescue medication. A minimum difference of 20% in the proportion of patients who were pain free was considered evidence of the clinical superiority of frovatriptan plus dexketoprofen (high dose) over frovatriptan alone. The 20% difference for the power was pre-specified in the study protocol and was determined by taking into account that there were not published or unpublished data of FroDex combination therapy versus Frova monotherapy; there were not specific requests coming from migraine guidelines for superiority trials (32). The only available data published of a combination therapy (SumaNapro) versus monotherapy (Suma) showed a mean difference within the range of 9% and 15%. For these reasons we considered a 20% difference a reasonable clinically important difference to reach (25–27,35). The study’s primary analysis population was the full analysis set (FAS) population that included all subjects randomized and treated for whom at least one post-dose intensification of headache was recorded. The per-protocol (PP) population consisted of all patients who treated a migraine attack without protocol violations. This population was identified prior to database lock and was used as a confirmatory analysis. Secondary study end points were: . Proportion of pain-free subjects at one hour and four hours, defined as subjects free of pain one hour and four hours before any rescue medication, according to IHS guidelines (3);
438 . Proportion of patients with headache relief at one, two and four hours, defined as the percentage of subjects with a decrease in headache from severe or moderate to mild or none within one hour, two hours and four hours, according to IHS guidelines (3); . Sustained pain free, defined as the percentages of subjects who were pain free within two hours with no use of rescue medication or recurrence within 24 hours and 48 hours, according to IHS guidelines (3); . Recurrence, defined according to IHS guidelines as a headache of any severity returning within 48 hours, in a subject who was pain free at two hours and who had not taken any rescue medication (3); . Proportion of subjects with resolution of nausea, vomiting, photophobia and phonophobia; . Proportion of subjects taking rescue medication; . Time to meaningful relief, defined as a reduction of at least two points on the four-point scale (i.e. from severe pain score of 3 at baseline to mild or no pain of score 1/0); . Speed of onset at 60, 90, 120 and 240 minutes, defined as a decrease of one point in pain intensity; . Subjects’ preference for treatments. Main and secondary variables were analyzed at a twosided significance level of 0.05. The tolerability analysis was conducted on all randomized patients and included the incidence of adverse events and changes in vital signs during the study. Continuous variables were summarized by computing mean values and their standard deviation (SD), while categorical variables were summarized by computing their absolute values and frequencies (as percentages). The efficacy assessments were made by the patient at the time of dosing (baseline) and at two, four, 24 and 48 hours after dosing. The data were analyzed using SASÕ version 9.2. The planned sample size of 300 randomized subjects (100 per group) (allowing for a drop-out rate of at least 20%) was chosen to provide the study with the statistical power to detect the possible superiority of the test drug (FroDex37.5) with respect to the reference treatment (Frova alone), on the percentage of subjects pain free at two hours before any rescue medication, as the primary variable, and assuming 20% as the margin of superiority and a power of almost 90% (88%). Thus, the test drug was to be considered superior to the reference one if the difference (test minus reference) in the primary variable was >20%. The primary variable was assessed by the FisherFreeman-Halton Exact test statistic using a 3 2 contingency table for tests of association and a 2 2 contingency table for comparisons between treatments. All other secondary parameters were assessed in the same
Cephalalgia 34(6) way as the primary variable. The level of significance was set at 0.05 for all analyses. The primary and all secondary parameters were assessed in the FAS population, which included all subjects randomized and treated for whom at least one post-dose intensification of headache was recorded. All p values for secondary end points are reported without adjustment for multiplicity.
Results A total of 314 patients, of the planned 300, were randomized: 106 in the Frova group, 105 in the FrovaDex25 group and 103 in the FroDex37.5 group. Table 1 shows the main demographic and clinical characteristics of the patients in the FAS population. Most of the subjects enrolled were females. A statistically significant difference was found in the gender population considering the three groups. This difference did not influence results of the primary end point. There were no statistically significant differences between the treatment groups in any other demographic or clinical characteristic.
Primary end point Overall comparison among treatments showed a statistically significant difference (p ¼ 0.003, FisherFreeman-Halton Exact test). In the FAS population, the proportion of patients who were pain free at two hours was 29% (27/93) with Frova, 51% (48/95) for FroDex25 (odds ratio (OR) ¼ 2.5 (1.37–4.5), p < 0.05) and also 51% (46/91) for FroDex37.5 (OR ¼ 2.5 (1.36– 4.6), p < 0.05) (Figure 2). There was not a statistically significant difference in the comparison between FroDex25 and FroDex37.5 (OR ¼ 1 (0.56–1.78), p ¼ 1).
Secondary end points The results of the analysis of secondary end points are summarized in Table 2. There was not a statistically significant difference in the comparison between FroDex25 and FroDex37.5 in all the secondary end points. FroDex 25 was better than Frova in nearly all of the secondary end points. In particular the proportions of pain free at four hours and of pain relief at one and two hours were significantly better (p < 0.05). Also in terms of sustained effect, more so at 24 than at 48 hours, FroDex25 was better than Frova. With respect to recurrence, however, the results are similar between the Frova and FroDex25 groups. FroDex37.5 was significantly better than Frova in nearly all of the secondary end points, including pain free at four hours and pain relief at one and two hours.
439
Tullo et al.
Table 1. Demographic and clinical data of the 279 patients in the FAS population at the time of randomization. Data are shown as mean (SD), or absolute (n) and relative frequency (%).
Ages (years) Females (n. %) Height (cm. mean SD) Weight (kg. mean SD) MIDAS score (mean SD) Presence of aura (n %) Intensity of attack Mild (n %) Moderate (n %) Severe (n %) Presence of nausea (n %) Presence of photophobia (n %) Presence of phonophobia (n %) Preventive therapy (n %) Antidepressant Antiepileptics Beta- blocking agents Triptan users (n %) NSAIDs users (n %)
Frovatriptan (93) n (%)
FroDex 25 mg (95) n (%)
FroDex 37.5 mg (91) n (%)
FAS (279) n (%)
All randomized (314)
PP (202) n (%)
38.3 9 89 (95) 164.4 5.8 61.1 8.7 23 16.9 9 (10)
38.2 10 84 (88)a* 165.8 17.6 61.4 10 25.6 29.4 2 (2)
40 10 75 (82)a* 166.4 17.7 63.5 12.1 23.1 16.6 5 (5)
38.8 10 248 (89) 165 7.1 62 10.4 23.9 21.8 16 (8)
38.6 10 272 (87) 166 7.4 62.2 10.4 24.3 23.1 20 (6)
39.2 10 178 (88) 166 7.4 62.3 10.5 25.4 24.1 11 (5)
8 (9) 58 (62) 27 ( 29) 45 (48) 64 (68) 58 (62)
6 (6) 62 (65) 27 (28) 47 (49) 61 (64) 62 (65)
3 (3) 57 (62) 31 (34) 42 (46) 63 (68) 53 (58)
17 (6) 177 (63) 85 (31) 134 (48) 188 (67) 173 (62)
18 (6) 197 (63) 99 (32) 149 (48) 211 (67) 194 (62)
11 (5) 122 (60) 69 (34) 95 (47) 138 (68) 129 (64)
8 (9) 7 (8) 3 (3) 66 (71) 28 (30)
9 (9) 6 (6) 3 (3) 68 (72) 19 (20)
10 10 10 62 22
27 (10) 23 (8) 16 (5) 196 (70) 69 (25)
30 (10) 25 (8) 19 (6) 218 (69) 84 (27)
16 (8) 15 (7) 12 (6) 132 (65) 41 (20)
(11) (11) (11) (68) (24)
a Statistically significant difference (p < 0.05) between the group treated with frovatriptan alone and the groups treated with combination therapy. FAS: full analysis set; FroDex: frovatriptan þ dexketoprofen; PP: per protocol. MIDAS: Migraine Disability Assessment; NSAIDs: nonsteroidal antiinflammatory drugs.
100 90 80
* 51%
Proportion (%)
70 60 50 40
* 51%
(48/95)
(46/91)
FroDex25
FroDex37.5
29%
(27/93)
30 20 10 0
Frova
Figure 2. Proportion (%) of pain free at two hours after administration of Frova, FroDex25 and FroDex37.5 in the 279 patients of the FAS population. Asterisks indicate a statistically significant difference (p < 0.05) between the group treated with frovatriptan alone and the groups treated with combination therapy. Frova: frovatriptan 2.5 mg alone; FroDex25: frovatriptan 2.5 mg þ dexketoprofen 25 mg; FroDex37.5: frovatriptan 2.5 mg þ dexketoprofen 37.5 mg; FAS: full analysis set.
440
Cephalalgia 34(6)
Table 2. Results for the secondary end points of the study.
Primary end point Pain free at two hours Secondary end point Pain free at one hour Pain free at four hours Pain relief at one houra Pain relief at two hoursa Pain relief at four hoursa Sustained pain free at 24 hours Sustained pain free at 48 hours Recurrence 48 hoursb Resolution of nausea at one hour Resolution of nausea at two hours Resolution of photophobia at one hour Resolution of photophobia at two hours Resolution of phonophobia at one hour Resolution of phonophobia at two hours Rescue medication Time to meaningful relief (hours) Speed of onset at one hour Speed of onset at 90 minutes Speed of onset at two hours Speed of onset at four hours Treatment good or excellent
Frovatriptan (93) n (%)
FroDex25 mg (95) n (%)
p
Frovatriptan (93) n (%)
FroDex37.5 mg (91) n (%)
p
27 (29)
48 (51)
Comparison of frovatriptan plus dexketoprofen (25 mg or 37.5 mg) with frovatriptan alone in the treatment of migraine attacks with or without aura: A randomized study
Cephalalgia 2014, Vol. 34(6) 434–445 ! International Headache Society 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102413515342 cep.sagepub.com
Vincenzo Tullo1, Fabio Valguarnera2, Piero Barbanti3, Pietro Cortelli4, Giuliano Sette5, Gianni Allais6, Florindo d’Onofrio7, Marcella Curone1, Dario Zava8, Deborha Pezzola8, Chiara Benedetto6, Fabio Frediani9 and Gennaro Bussone1 Abstract Background: Drugs for migraine attacks include triptans and NSAIDs; their combination could provide greater symptom relief. Methods: A total of 314 subjects with history of migraine, with or without aura, were randomized to frovatriptan 2.5 mg alone (Frova), frovatriptan 2.5 mg þ dexketoprofen 25 mg (FroDex25) or frovatriptan 2.5 mg þ dexketoprofen 37.5 mg (FroDex37.5) and treated at least one migraine attack. This was a multicenter, randomized, double-blind, parallel-group study. The primary end point was the proportion of pain free (PF) at two hours. Secondary end points were PF at one and four hours, pain relief (PR) at one, two, four hours, sustained PF (SPF) at 24 and 48 hours, recurrence at 48 hours, resolution of nausea, photophobia and phonophobia at two and four hours, the use of rescue medication and the judgment of the treatment. Results: The results were assessed in the full analysis set (FAS) population, which included all subjects randomized and treated for whom at least one post-dose intensity of headache was recorded. The proportions of subjects PF at two hours (primary end point) were 29% (27/93) with Frova compared with 51% (48/95 FroDex25 and 46/91 FroDex37.5) with each combination therapies (p < 0.05). Proportions of SPF at 24 hours were 24% (22/93) for Frova, 43% (41/95) for FroDex25 (p < 0.001) and 42% (38/91) for FroDex37.5 (p < 0.05). SPF at 48 hours was 23% (21/93) with Frova, 36% (34/95) with FroDex25 and 33% (30/91) with FroDex37.5 (p ¼ NS). Recurrence was similar for Frova (22%, 6/27), FroDex25 (29%, 14/48) and FroDex37.5 (28%, 13/46) (p ¼ NS), meaning a lack of improvement with the combination therapy. Statistical adjustment for multiple comparisons was not performed. No statistically significant differences were reported in the occurrence of total and drug-related adverse events. FroDex25 and FroDex37.5 showed a similar efficacy both for primary and secondary end points. There did not seem to be a dose response curve for the addition of dexketoprofen. Conclusion: FroDex improved initial efficacy at two hours compared to Frova whilst maintaining efficacy at 48 hours in this study. Tolerability profiles were comparable. Intrinsic pharmacokinetic properties of the two single drugs contribute to this improved efficacy profile.
1
Department of Clinical Neuroscience, National Neurological Institute Carlo Besta, Italy 2 Sestri Ponente Hospital ‘‘Padre Antero Micone’’, Italy 3 Unit for treatment and research of headaches and pain, IRCCS San Raffaele Pisana, Italy 4 Neurological Clinic, Department of Neurological Science, University of Bologna, Italy 5 Sant’Andrea Hospital, Italy
6 Department of Gynecology and Obstetrics, Women’s Headache Center, University of Turin, Italy 7 San Giuseppe Moscati Hospital, Italy 8 Istituto Luso Farmaco d’Italia, Peschiera Borromeo, Italy 9 Ospedale S. Carlo Borromeo, Italy
Corresponding author: Vincenzo Tullo, Department of Clinical Neuroscience, National Neurological Institute Carlo Besta, Via Celoria 11, 20133 Milano, Italy. Email: [email protected]
435
Tullo et al. Keywords Frovatriptan, dexketoprofen, migraine attacks, triptans, NSAIDs Date received: 25 June 2013; revised: 6 August 2013; 13 September 2013; 7 October 2013; accepted: 11 October 2013
Introduction Migraine affects approximately 18% of women and 6% of men in Western countries (1). The prevalence peaks in subjects between 25 and 55 years old. The burden of migraine is enormous; in the United States (US) migraine sufferers spend a total of 112 million days bedridden and the annual cost of missed work or reduced productivity is $5.6 billion to $17.2 billion (1,2). The International Headache Society (IHS) criteria for diagnosing migraine (3) are the most widely used diagnostic criteria around the world. Drugs effective for treating migraine attacks include triptans, analgesics (such as nonsteroidal inflammatory drugs (NSAIDs)), ergot derivatives and antiemetics (4). Triptans, marketed in the early 1990s, were a major advance in the treatment of moderate-severe acute migraine attacks (4). They are selective 5-HT1B/D agonists. Seven triptans are available, being, theoretically, similar, but patients note differences in effectiveness and in tolerance (5). Frovatriptan is one of the newest triptans and its distinct pharmacokinetic and pharmacodynamics profile means that it has the clinical potential for a long duration of action and a low likelihood of side effects and drug interactions (6). The elimination half-life of frovatriptan is five times that of other triptans, while the time to maximum concentration (tmax) is similar to other triptans when given orally (5,7–10). NSAIDs and other simple analgesics are indicated for the treatment of mild or moderate migraine attacks (4). Dexketoprofen works by blocking the action of cyclooxygenase (COX), which is involved in the production of prostaglandins, and thereby reduces inflammation and pain (11,12). Dexketoprofen maximum plasma concentrations are observed around 30 minutes after an oral dose. Its elimination half-life, however, is quite short (13). Dexketoprofen proved to be effective and very fast in reducing pain intensity and accompanying symptoms in 42 women affected by migraine with or without aura (14). The complexity of the pathophysiology of migraine partially explains why none of the currently available monotherapies provides broad coverage of the multiple pathogenic processes in migraine (15–25).
A therapy that targets multiple mechanisms may confer advantages over monotherapy, and triptans and NSAIDs target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. This possibility is supported by the results of several clinical studies, including those on the concomitant use of sumatriptan succinate with naproxen sodium and rizatriptan with rofecoxib (26–30). The rationale for combining dexketoprofen with frovatriptan is linked to the intrinsic pharmacokinetic properties of the two drugs; dexketoprofen is absorbed rapidly and contributes to the early efficacy of the combination, whereas frovatriptan persists longer and so provides sustained efficacy with less recurrence. The aims of this study were to evaluate the efficacy and tolerability of the combination therapy frovatriptan plus dexketoprofen over frovatriptan alone in the acute treatment of migraine attacks.
Methods Study population The study recruited subjects of male or female gender, 18–65 years old, with a current history of migraine with or without aura, according to IHS 2004 criteria, and with at least one but no more than six migraine attacks per month for six months prior to entering the study. Figure 1 shows the study flowchart. Patients could not be enrolled in the study if they: (a) had coronary artery or cerebrovascular disease; (b) had uncontrolled hypertension; (c) had other types of headache in addition to migraine with or without aura; (d) were taking ergotamine (or its derivatives), St John’s Wort (Hypericum perforatum), monoamine oxidase (MAO)-inhibitors, NSAIDs (COX-2 inhibitors), oral corticosteroids, warfarin or other coumarins, selective serotonin reuptake inhibitors, or antiaggregant agents such as aspirin, heparin, lithium, methotrexate, hydantoins and sulphonamides; (e) had severe liver or renal impairment; (f) had a history of alcohol, analgesic or psychotropic drug abuse; (g) had known hypersensitivity to either of the study drugs or to any other NSAIDs; (h) had active peptic ulcer/bleeding or a history of gastrointestinal bleeding or perforation related to NSAID therapies; (i) had bronchial asthma; (j) were pregnant or breast feeding.
436
Cephalalgia 34(6)
PATIENTS SCREENED N = 321 - Violation of selection criteria (N = 2) - Other (N = 5) PATIENTS RANDOMIZED N = 314
PATIENTS ASSIGNED TO GROUP:
PATIENTS ASSIGNED TO GROUP:
PATIENTS ASSIGNED TO GROUP:
Frovatriptan
F + DXP 25 mg
F + DXP 37.5 mg
N = 106
N = 105
N = 103
COMPLETED
COMPLETED
COMPLETED
N = 106
N = 105
N = 103
Exclusion from FAS Population: - No attacks treated (N = 12) - Lack of efficacy data (N=1)
Exclusion from FAS Population: - No attacks treated (N = 10)
Exclusion from FAS Population: - No attacks treated (N = 11) - Lack of efficacy data (N=1)
FAS Population
FAS Population
FAS Population
N = 93
N = 95
N = 91
Exclusion from PP Population: - Prohibited treatments (N =4) - Inconsistency diaries (N=18) - Prohibited treatments+Diaries (N =1) - Lab test after V0+Diaries (N=1) - Prohibited treatments+wrong visit interval (N =2)
Exclusion from PP Population: - Prohibited treatments (N =2) - Inconsistency diaries (N=22) - Informed consent’s date not consistent (N=1) - Migraine attack after 30 days (=1) - Prohibited treatments+Migraine attack after 30 days (=1) - Prohibited treats+Diaries (N =3) - Wrong visit interval+Diaries (N=1)
Exclusion from PP Population: - Protocol criteria violation (N = 1) - Prohibited treatments (N =2) - Inconsistency diaries (N=13) - Informed consent’s date not consistent (N=1) - Prohibited treats+Diaries (N =2) - Wrong visit interval+Diaries (N=1)
PP Population
PP Population
PP Population
N = 67
N = 64
N = 71
Figure 1. Flow diagram of participants throughout the study. FAS: full analysis set; PP: per protocol; F: frovatriptan; DXP: dexketoprofen.
Written informed consent was obtained from all patients prior to their inclusion in the study. The study was approved by the independent institutional review boards of the centers in which the study
was carried out. The study was conducted according to the Declaration of Helsinki and Good Clinical Practice and was registered internationally (Eudract number 2009-011577-32).
437
Tullo et al.
Study design This was a multicenter, randomized, double-blind, active-controlled, three parallel-group, phase 3 study performed in 25 Italian centers from July 2009 to April 2010. Over-encapsulation was used to ensure blinding. This active treatment dose-comparison concurrent control study compared frovatriptan 2.5 mg þ dexketoprofen 25 mg (FroDex25) or frovatriptan 2.5 mg þ dexketoprofen 37.5 mg (FroDex37.5) to frovatriptan 2.5 mg þ placebo (Frova), in acute treatment of migraine with or without aura attacks in three parallel groups of 100 subjects each. The study protocol also foresaw a comparison between FroDex25 and FroDex37.5. After the screening visit, subjects were assigned by the investigators to one of the three treatment groups using randomization lists prepared by InnoPharma s.r.l. generated using three-subject blocks to balance the treatments. The lists were provided to all sites before the start of the study. Code-break envelopes were provided to the sites and could be opened in the case of an emergency. To keep the patients and study investigators blind to the treatment, the study drugs were over-encapsulated. Frovatriptan, dexketoprofen and placebo tablets were over-encapsulated in capsules suitable to keep the blinding. Two colors of capsules were used: white and red. The extemporary combination of frovatriptan 2.5 mg þ dexketoprofen 37.5 mg, frovatriptan 2.5 mg þ dexketoprofen 25 mg, frovatriptan 2.5 mg þ placebo was provided in indistinguishable carton boxes identified by the randomization numbers, each containing one treatment dose blister with two capsules: a red and a white one. All study end point parameters were recorded in a personal diary and, for the intensity of the headache attack, a four-point rating scale recommended by the IHS (0 ¼ no headache, 1 ¼ mild headache, 2 ¼ moderate headache, 3 ¼ severe headache) was used. Similar scales were used for assessment of the associated symptoms (nausea, photophobia and phonophobia). The active controlled design was chosen in accordance with guidelines on the choice of control groups in studies aimed at demonstrating superiority of a new treatment when an established treatment already exists (3,4). The two doses of 25 mg and 37.5 mg of dexketoprofen were chosen based on available literature data, and on the results from previous pre-clinical and clinical studies (12). The frovatriptan dose of 2.5 mg is the dose recommended in the SmPC (31). During the randomization visit, after signing written informed consent, subjects provided their clinical, medication and migraine history. Physical and neurological examinations and a pregnancy test (if appropriate) were performed. Blood pressure and heart rate
were measured for all subjects. The degree of migraine-associated disability was also determined, using the Migraine Disability Assessment (MIDAS) questionnaire. At the end of the visit a headache diary was dispensed with the study medication in order to document the characteristics of the headache pain and associated symptoms, and subjects were instructed to take the study medication and complete the diary for the first migraine attack that occurred during the study period (i.e. within one month from randomization). The study treatment was self-administered orally in single administration as early as possible after the onset of the migraine headache. During the study, three visits to the clinical center were scheduled: one at the screening, one at the randomization visit and a follow-up visit between 72 hours and 14 days (2) after the migraine attack.
Data analysis The primary efficacy variable to assess the possible superiority of frovatriptan plus dexketoprofen (high and low doses) over frovatriptan alone was the percentage of subjects pain free at two hours before any rescue medication. A minimum difference of 20% in the proportion of patients who were pain free was considered evidence of the clinical superiority of frovatriptan plus dexketoprofen (high dose) over frovatriptan alone. The 20% difference for the power was pre-specified in the study protocol and was determined by taking into account that there were not published or unpublished data of FroDex combination therapy versus Frova monotherapy; there were not specific requests coming from migraine guidelines for superiority trials (32). The only available data published of a combination therapy (SumaNapro) versus monotherapy (Suma) showed a mean difference within the range of 9% and 15%. For these reasons we considered a 20% difference a reasonable clinically important difference to reach (25–27,35). The study’s primary analysis population was the full analysis set (FAS) population that included all subjects randomized and treated for whom at least one post-dose intensification of headache was recorded. The per-protocol (PP) population consisted of all patients who treated a migraine attack without protocol violations. This population was identified prior to database lock and was used as a confirmatory analysis. Secondary study end points were: . Proportion of pain-free subjects at one hour and four hours, defined as subjects free of pain one hour and four hours before any rescue medication, according to IHS guidelines (3);
438 . Proportion of patients with headache relief at one, two and four hours, defined as the percentage of subjects with a decrease in headache from severe or moderate to mild or none within one hour, two hours and four hours, according to IHS guidelines (3); . Sustained pain free, defined as the percentages of subjects who were pain free within two hours with no use of rescue medication or recurrence within 24 hours and 48 hours, according to IHS guidelines (3); . Recurrence, defined according to IHS guidelines as a headache of any severity returning within 48 hours, in a subject who was pain free at two hours and who had not taken any rescue medication (3); . Proportion of subjects with resolution of nausea, vomiting, photophobia and phonophobia; . Proportion of subjects taking rescue medication; . Time to meaningful relief, defined as a reduction of at least two points on the four-point scale (i.e. from severe pain score of 3 at baseline to mild or no pain of score 1/0); . Speed of onset at 60, 90, 120 and 240 minutes, defined as a decrease of one point in pain intensity; . Subjects’ preference for treatments. Main and secondary variables were analyzed at a twosided significance level of 0.05. The tolerability analysis was conducted on all randomized patients and included the incidence of adverse events and changes in vital signs during the study. Continuous variables were summarized by computing mean values and their standard deviation (SD), while categorical variables were summarized by computing their absolute values and frequencies (as percentages). The efficacy assessments were made by the patient at the time of dosing (baseline) and at two, four, 24 and 48 hours after dosing. The data were analyzed using SASÕ version 9.2. The planned sample size of 300 randomized subjects (100 per group) (allowing for a drop-out rate of at least 20%) was chosen to provide the study with the statistical power to detect the possible superiority of the test drug (FroDex37.5) with respect to the reference treatment (Frova alone), on the percentage of subjects pain free at two hours before any rescue medication, as the primary variable, and assuming 20% as the margin of superiority and a power of almost 90% (88%). Thus, the test drug was to be considered superior to the reference one if the difference (test minus reference) in the primary variable was >20%. The primary variable was assessed by the FisherFreeman-Halton Exact test statistic using a 3 2 contingency table for tests of association and a 2 2 contingency table for comparisons between treatments. All other secondary parameters were assessed in the same
Cephalalgia 34(6) way as the primary variable. The level of significance was set at 0.05 for all analyses. The primary and all secondary parameters were assessed in the FAS population, which included all subjects randomized and treated for whom at least one post-dose intensification of headache was recorded. All p values for secondary end points are reported without adjustment for multiplicity.
Results A total of 314 patients, of the planned 300, were randomized: 106 in the Frova group, 105 in the FrovaDex25 group and 103 in the FroDex37.5 group. Table 1 shows the main demographic and clinical characteristics of the patients in the FAS population. Most of the subjects enrolled were females. A statistically significant difference was found in the gender population considering the three groups. This difference did not influence results of the primary end point. There were no statistically significant differences between the treatment groups in any other demographic or clinical characteristic.
Primary end point Overall comparison among treatments showed a statistically significant difference (p ¼ 0.003, FisherFreeman-Halton Exact test). In the FAS population, the proportion of patients who were pain free at two hours was 29% (27/93) with Frova, 51% (48/95) for FroDex25 (odds ratio (OR) ¼ 2.5 (1.37–4.5), p < 0.05) and also 51% (46/91) for FroDex37.5 (OR ¼ 2.5 (1.36– 4.6), p < 0.05) (Figure 2). There was not a statistically significant difference in the comparison between FroDex25 and FroDex37.5 (OR ¼ 1 (0.56–1.78), p ¼ 1).
Secondary end points The results of the analysis of secondary end points are summarized in Table 2. There was not a statistically significant difference in the comparison between FroDex25 and FroDex37.5 in all the secondary end points. FroDex 25 was better than Frova in nearly all of the secondary end points. In particular the proportions of pain free at four hours and of pain relief at one and two hours were significantly better (p < 0.05). Also in terms of sustained effect, more so at 24 than at 48 hours, FroDex25 was better than Frova. With respect to recurrence, however, the results are similar between the Frova and FroDex25 groups. FroDex37.5 was significantly better than Frova in nearly all of the secondary end points, including pain free at four hours and pain relief at one and two hours.
439
Tullo et al.
Table 1. Demographic and clinical data of the 279 patients in the FAS population at the time of randomization. Data are shown as mean (SD), or absolute (n) and relative frequency (%).
Ages (years) Females (n. %) Height (cm. mean SD) Weight (kg. mean SD) MIDAS score (mean SD) Presence of aura (n %) Intensity of attack Mild (n %) Moderate (n %) Severe (n %) Presence of nausea (n %) Presence of photophobia (n %) Presence of phonophobia (n %) Preventive therapy (n %) Antidepressant Antiepileptics Beta- blocking agents Triptan users (n %) NSAIDs users (n %)
Frovatriptan (93) n (%)
FroDex 25 mg (95) n (%)
FroDex 37.5 mg (91) n (%)
FAS (279) n (%)
All randomized (314)
PP (202) n (%)
38.3 9 89 (95) 164.4 5.8 61.1 8.7 23 16.9 9 (10)
38.2 10 84 (88)a* 165.8 17.6 61.4 10 25.6 29.4 2 (2)
40 10 75 (82)a* 166.4 17.7 63.5 12.1 23.1 16.6 5 (5)
38.8 10 248 (89) 165 7.1 62 10.4 23.9 21.8 16 (8)
38.6 10 272 (87) 166 7.4 62.2 10.4 24.3 23.1 20 (6)
39.2 10 178 (88) 166 7.4 62.3 10.5 25.4 24.1 11 (5)
8 (9) 58 (62) 27 ( 29) 45 (48) 64 (68) 58 (62)
6 (6) 62 (65) 27 (28) 47 (49) 61 (64) 62 (65)
3 (3) 57 (62) 31 (34) 42 (46) 63 (68) 53 (58)
17 (6) 177 (63) 85 (31) 134 (48) 188 (67) 173 (62)
18 (6) 197 (63) 99 (32) 149 (48) 211 (67) 194 (62)
11 (5) 122 (60) 69 (34) 95 (47) 138 (68) 129 (64)
8 (9) 7 (8) 3 (3) 66 (71) 28 (30)
9 (9) 6 (6) 3 (3) 68 (72) 19 (20)
10 10 10 62 22
27 (10) 23 (8) 16 (5) 196 (70) 69 (25)
30 (10) 25 (8) 19 (6) 218 (69) 84 (27)
16 (8) 15 (7) 12 (6) 132 (65) 41 (20)
(11) (11) (11) (68) (24)
a Statistically significant difference (p < 0.05) between the group treated with frovatriptan alone and the groups treated with combination therapy. FAS: full analysis set; FroDex: frovatriptan þ dexketoprofen; PP: per protocol. MIDAS: Migraine Disability Assessment; NSAIDs: nonsteroidal antiinflammatory drugs.
100 90 80
* 51%
Proportion (%)
70 60 50 40
* 51%
(48/95)
(46/91)
FroDex25
FroDex37.5
29%
(27/93)
30 20 10 0
Frova
Figure 2. Proportion (%) of pain free at two hours after administration of Frova, FroDex25 and FroDex37.5 in the 279 patients of the FAS population. Asterisks indicate a statistically significant difference (p < 0.05) between the group treated with frovatriptan alone and the groups treated with combination therapy. Frova: frovatriptan 2.5 mg alone; FroDex25: frovatriptan 2.5 mg þ dexketoprofen 25 mg; FroDex37.5: frovatriptan 2.5 mg þ dexketoprofen 37.5 mg; FAS: full analysis set.
440
Cephalalgia 34(6)
Table 2. Results for the secondary end points of the study.
Primary end point Pain free at two hours Secondary end point Pain free at one hour Pain free at four hours Pain relief at one houra Pain relief at two hoursa Pain relief at four hoursa Sustained pain free at 24 hours Sustained pain free at 48 hours Recurrence 48 hoursb Resolution of nausea at one hour Resolution of nausea at two hours Resolution of photophobia at one hour Resolution of photophobia at two hours Resolution of phonophobia at one hour Resolution of phonophobia at two hours Rescue medication Time to meaningful relief (hours) Speed of onset at one hour Speed of onset at 90 minutes Speed of onset at two hours Speed of onset at four hours Treatment good or excellent
Frovatriptan (93) n (%)
FroDex25 mg (95) n (%)
p
Frovatriptan (93) n (%)
FroDex37.5 mg (91) n (%)
p
27 (29)
48 (51)
